Microbial α-Glucosidase Inhibitors: Chemistry, Biochemistry, and Therapeutic Potential

Truscheit, Ernst; Hillebrand, I.; Junge, Bodo; Müller, Lutz; Puls, W.; Schmidt, Delf

doi:10.1007/978-3-642-73461-8_2

Cited by 40 publications

(24 citation statements)

References 105 publications

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“…With acarbose, it is a common observation that gastrointestinal adverse effects tend to decrease with time, and finally almost disappear.F'l This phenomenon is not due to reduced efficacy of acarbose, but to an adaptation of the carbohydrate digestive capacity.F'] Because of the lack of available substrate, a-glucosidase activity is much lower in the distal part of the small intestine of normally fed rats compared with proximal segments.l 92 , 931 In animal studies, acarbose treatment appears to promote an adaptational increase in levels of a-glucosidase enzymes in the distal small bowel, [3,94] thus improving carbohydrate digestive capacity and drug tolerability.…”

Section: Adverse Effectsmentioning

confidence: 99%

Pharmacokinetic-Pharmacodynamic Relationships of Acarbose

Salvatore

Giugliano

1996

Clinical Pharmacokinetics

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Acarbose represents a new pharmacological approach to achieving the metabolic benefits of a slower carbohydrate absorption in diabetes, by acting as a potent, competitive inhibitor of intestinal alpha-glucosidases. Acarbose molecules attach to the carbohydrate binding sites of alpha-glucosidases, with an affinity constant that is much higher than that of the normal substrate. Because of the reversible nature of the inhibitor-enzyme interaction, the conversion of oligosaccharides to monosaccharides is only delayed rather than completely blocked. Acarbose has the structural features of a tetrasaccharide and does not cross the enterocytes after ingestion. Thus, its pharmacokinetic properties are well suited to the pharmacological action directed exclusively towards the intestinal glucosidases. The most important clinical consequence of the delayed carbohydrate digestion caused by acarbose is the attenuation of postprandial increases in blood glucose levels. Other effects have also been described: a decreased beta-pancreatic response to meals, and influences on gut hormone secretion and plasma lipid levels. Gastrointestinal discomfort is frequently reported as an adverse effect of acarbose administration, but incidence usually decreases with time. The suitability of acarbose for improving glucose homeostasis as an adjunct to dietary control or to administration of sulphonylureas or insulin has been extensively studied in patients both with type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus. Acarbose can be used as first-line therapy in patients with type 2 diabetes which is poorly controlled by diet alone. Moreover, the lack of bodyweight gain or hypoglycaemic effects reported during acarbose treatment may be advantageous for obese or elderly patients. Finally, the reduction in fluctuations of glucose levels throughout the day may help to control type 1 diabetes in patients with 'brittle diabetes'. Long term prospective studies are still needed to confirm these indications and the usefulness of acarbose in conditions other than diabetes, notably reactive hypoglycaemia and dumping syndrome.

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Section: Adverse Effectsmentioning

confidence: 99%

Pharmacokinetic-Pharmacodynamic Relationships of Acarbose

Salvatore

Giugliano

1996

Clinical Pharmacokinetics

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“…[5] As ar esult of this competitive inhibition, the activity of a-glucosidase in the mucous membrane of the smalli ntestine is inhibited. The complexes have am uch stronger affinity than carbohydrate-glucosidase complexes.…”

Section: Introductionmentioning

confidence: 99%

Recent Advances in Synthetic α‐Glucosidase Inhibitors

Liu

2017

ChemMedChem

112

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Over the past few years, the number of people diagnosed with type 2 diabetes has increased owing to an unhealthy diet, a limited amount of exercise, and obesity. The search for novel and efficient antidiabetes agents has become an urgent task for scientists. Among the antidiabetes drugs, α-glucosidase inhibitor drugs have been proven to have many advantages over other drugs, and therefore, a large number of new compounds as α-glucosidase inhibitors has recently been reported. In this review, we summarize these newly found α-glucosidase inhibitors and their structure-activity relationships in antidiabetic studies and provide better structures for α-glucosidase inhibitors or even preclinical candidates. Beyond that, some enlightening strategies for the synthesis of relevant compounds are highlighted.

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“…It was also discovered in the culture broths of various species of Streptomyces lavendulae (MATSUMURA et al 1979c;MlTsuo and SAWAO 1980;MURAO and MIYATA 1980;EZURE et al 1985) and S. subrutilus (HARDICK et al 1991(HARDICK et al ,1992. Compared with nojirimycin, 1-deoxynojirimycin is a weaker inhibitor of nonmammalian and mammalian ß-glucosidases (NIWA et al 1970;see also: TRUSCHEIT et al 1981;MÜLLER 1985;SCOFIELD et al 1986;TRUSCHEIT 1987;ELBEIN 1987;TRUSCHEIT et al 1988;YOSHIKUNI et al 1988;LEGLER 1990;NISHIMURA 1991;YOSHIKUNI 1991;ROBINSON et al 1992;HUGHES and RUDGE 1994). However, the discovery of the inhibitory effect on mammalian a-glucosidases opened the possibility of a therapeutic application for 1-deoxynojirimycin.…”

Section: I-deoxynojirimycinmentioning

confidence: 90%

Chemistry and Structure-Activity Relationships of Glucosidase Inhibitors

Junge¹,

Matzke²,

Stoltefuß³

1996

Oral Antidiabetics

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A. IntroductionWhen intestinal sucrase and pancreatic a-amylase were identified at Bayer as new targets for improved diabetes therapy (PULS et al. 1973), the problem remained of the best way to find a potent and selective inhibitor of these enzymes. The medicinal chemist today has two alternatives in the search for a first lead compound, firstly the screening of thousands of compounds with maximum structural diversity in a random screening approach, or secondly the rational design of a lead compound, when the biochemical mechanism and the structure of the enzyme are weIl known. In the late 1960s, when we started to look for such potent and selective inhibitors, we had to choose the random screening approach, relying mainly on testing of extracts of the culture broths of microorganisms.Today the mechanism of enzymatic splitting of sucrose by intestinal sucrase is fairly weIl understood. First the glucosidic oxygen atom of sucrose is protonated via a carboxyl group of the enzyme. The splitting of the glucosidic C-O bond is further facilitated by the glucosyl cation being stabilized by a second carboxylate group of the enzyme (COGOLI and SEMENZA 1975). FinaIly, the glucosyl cation reacts with water to give the products 0-glucose and o-fructose. The protonated sucrose molecule land the glucosyl cation 11 are two high-energy intermediates of the enzymatic reaction. Today we know that mimics of such high-energy intermediates are often potent inhibitors of the enzyme. Accordingly, compounds similar in structure to o-glucose but with an easily protonated basic N-atom either in the position of the anomeric oxygen atom (inhibitor type I) or in the position of the ring oxygen atom (inhibitor type 11) should be potent inhibitors of sucrase (Fig. 1). Interestingly, both types of inhibitors represented by either acarbose or I-deoxynojirimycin were found in our random screening. In the foIlowing sections these two types of inhibitors are not discussed in a historical order but under structural criteria. Not included in this discussion are the a-amylase inhibitors of protein nature because there is no evidence that they will find any therapeutic application.

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Microbial α-Glucosidase Inhibitors: Chemistry, Biochemistry, and Therapeutic Potential

Cited by 40 publications

References 105 publications

Pharmacokinetic-Pharmacodynamic Relationships of Acarbose

Pharmacokinetic-Pharmacodynamic Relationships of Acarbose

Recent Advances in Synthetic α‐Glucosidase Inhibitors

Chemistry and Structure-Activity Relationships of Glucosidase Inhibitors

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